Via AAAS ID

This article is available to AAAS members. If you are a AAAS Member use your via AAAS ID and password to log in. Not a member? Click here to join.

Via your Institution

Log in through your institution

If your organization uses OpenAthens, you can log in using your OpenAthens username and password. To check if your institution is supported, please see this list. Contact your library for more details.

Log in through your institution

You may be able to gain access using your login credentials for your institution. Contact your library if you do not have a username and password.

Free with registration

Science Translational Medicine research is available free with registration one year after initial publication. To get your free access please visit our registration form.

Tidy telomeres make for healthier lungs

Telomeres are the protective caps that prevent the ends of chromosomes from unraveling. People carrying mutations in the protein or RNA component of telomerase, the enzyme that makes telomeres have short telomeres and a serious and often fatal lung disease—pulmonary fibrosis. Now, Stanley et al. find in several patients that other mutations, specifically those that interfere with RNA biogenesis, can also cause both short telomeres and lung disease. This work expands our understanding of how telomeres are maintained and their role in human disease.

Abstract

Chronic obstructive pulmonary disease and pulmonary fibrosis have been hypothesized to represent premature aging phenotypes. At times, they cluster in families, but the genetic basis is not understood. We identified rare, frameshift mutations in the gene for nuclear assembly factor 1, NAF1, a box H/ACA RNA biogenesis factor, in pulmonary fibrosis–emphysema patients. The mutations segregated with short telomere length, low telomerase RNA levels, and extrapulmonary manifestations including myelodysplastic syndrome and liver disease. A truncated NAF1 was detected in cells derived from patients, and, in cells in which the frameshift mutation was introduced by genome editing, telomerase RNA levels were reduced. The mutant NAF1 lacked a conserved carboxyl-terminal motif, which we show is required for nuclear localization. To understand the disease mechanism, we used CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein-9 nuclease) to generate Naf1+/− mice and found that they had half the levels of telomerase RNA. Other box H/ACA RNA levels were also decreased, but rRNA pseudouridylation, which is guided by snoRNAs, was intact. Moreover, first-generation Naf1+/− mice showed no evidence of ribosomal pathology. Our data indicate that disease in NAF1 mutation carriers is telomere-mediated; they show that NAF1 haploinsufficiency selectively disturbs telomere length homeostasis by decreasing the levels of telomerase RNA while sparing rRNA pseudouridylation.